Project Summary/Abstract Acne is one of the most common diseases worldwide, affecting 85% of adolescents and often persisting into adulthood. Acne is responsible for a greater global burden of disease than psoriasis, cellulitis, and melanoma. While mild acne can usually be managed with topical medications, moderate to severe acne often requires treatment with systemic agents such as oral antibiotics, hormonal therapies, and isotretinoin. Remarkably, while these agents are a standard part of care, there are very few randomized clinical trials showing efficacy and none that show comparative effectiveness between these commonly used agents; the Institute of Medicine has identified this area as one of the top priorities for comparative effectiveness research. Previous work by our group has shown oral antibiotics are the most common systemic agent used in the treatment of acne and patients frequently use them for more than one year. In fact, dermatologists prescribe more antibiotics per capita than any other specialty. However, prolonged antibiotic use may be associated with a variety of adverse outcomes including bacterial antibiotic resistance, pharyngitis, collagen vascular illnesses, inflammatory bowel disease, and breast and colon cancer. As a result, there is growing international interest and attention specifically from the Centers for Disease Control regarding improving antibiotic stewardship in the outpatient setting and multiple clinical guidelines for acne have recommended reducing the use of antibiotics through the use of non-antimicrobial therapies and by limiting the duration of therapy. For women with moderate to severe acne, spironolactone may represent an effective, well-tolerated alternative to oral antibiotics. Developed as a potassium-sparing diuretic, for many years it has also been used off-label for acne due to its impact on hormonal pathogenesis of this disease. However, despite expert opinion supporting the use of spironolactone in the treatment of acne, its use remains relatively uncommon and clinical evidence demonstrating the effectiveness of spironolactone is limited to small, often retrospective studies. Trials comparing the effectiveness of spironolactone to that of other agents such as oral antibiotics are lacking. Our ultimate goal is to complete the necessary planning and preparation to conduct a novel, prospective, randomized clinical trial evaluating the comparative effectiveness of spironolactone and oral tetracycline-class antibiotics in the treatment of acne in adult women. No such study has previously been conducted. The results of this study would have substantial implications for the treatment of acne and antibiotic stewardship. In addition, this study may allow us to monitor for the timing of the development of antibiotic resistance in a healthy population of patients treated with extended courses of antibiotics and to evaluate the impact of prolonged exposure to oral antibiotics on the microbiome. Our proposed study could significantly influence healthcare practice with respect to the treatment of moderate to severe acne in women and inform policy regarding more appropriate use of antibiotics throughout medicine.